Process for the preparation of 3-{2-′4- (6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyllethyl}-6,7,8,9-tetrahydro-2-methyl-4h-pyrido′1,2-methyl-4h-pyrido′,2-a!pyrimidin-4-one

ABSTRACT

The invention relates to a process for the preparation of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one of the Formula (I), and pharmaceutically acceptable acid addition salts thereof by subjecting the oxime of the Formula (II), to ring-closure in the presence of an alkali hydroxide, alkali carbonate or alkali-C 1-4  alkoxide in an inert organic solvent, converting the base of the Formula I thus obtained into an acid addition salt or setting free the base of the Formula I from an acid addition salt thereof which comprises reacting a halogen derivative of the general Formula (XIV), (wherein Hal is halogen) with piperidine oxime derivative of the Formula (V), or an acid addition salt thereof in the presence of a base, and using by the ring-closure of the oxime of the Formula II formed a C 1-4 -alkanol as inert solvent. The process of the present invention enables the economical preparation of a product having a purity suitable for pharmaceutical purposes.

TECHNICAL FIELD OF THE INVENTION

The invention relates to the preparation of3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.

The compound3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneof the Formula

is a well-known antipsychotic agent having the INN (InternationalNon-Proprietory Name) risperidone which can be used for the treatment ofdiseases related to serotonin release.

TECHNICAL BACKGROUND OF THE INVENTION

Several processes for the preparation of risperidone of the Formula Iare disclosed in HU-P 195,793 and the corresponding EP-P 196,132.According to one of said processes a reactive derivative of the generalFormula

(wherein W is a reactive group e.g. halogen or an O-sulfonic acid estergroup) is reacted in an inert solvent with a benzisoxazol derivative ofthe Formula

The disadvantage of said process is that the benzisoxazol derivative ofthe Formula IV is prepared by boiling the corresponding piperidine oximederivative of the Formula

in a strongly alkaline medium and in the course of this reaction notonly the desired fluorine atom in the ortho-position reactsbut—according to our experiments—the fluorine atom in the para-positiontakes also part in the reaction at a rate of about 5%, to yield thedimer of the Formula

As shown in comparative Example 1 said dimer of the Formula VIcontaminates the desired benzisoxazol derivative of the Formula IV. Thedimer of the Formula VI is significantly less soluble than thebenzisoxazol of the Formula IV and therefore practically it cannot beremoved by recrystallization. Consequently, on converting thebenzisoxazol derivative of the Formula IV contaminated with the dimer ofthe Formula VI to risperidone, said end-product contains about 3% of theimpurity dimer of the Formula

Since the dimer of the Formula VII is much less soluble thanrisperidone, it is practically impossible to remove the dimer of theFormula VII from risperidone. This is clearly shown in comparativeExample 2.

According to another known process risperidone is prepared by reactingthe amine of the Formula

with a diketone of the general Formula

(wherein L is a leaving group). However, the preparation of the diketoneof the Formula IX is neither described in the prior art citation nor isit exemplified and therefore this process is but of theoreticalimportance.

According to a further known process a compound of the general Formula

(wherein L₁ is a leaving group) is reacted with a piperidine derivativeof the general Formula

(wherein L is a leaving group). The prior art lacks an enablingdisclosure and for this reason the skilled art worker is not in theposition to carry out said process.

ES-P 2,050,069 aims to overcome the disadvantages of the knownprocedures. According to said Spanish patent a reactive derivative ofthe general Formula III is reacted with the ketone of the Formula

whereupon the piperidone derivative of the Formula

formed is reacted with hydroxylamine and finally the oxime of theFormula

thus obtained is subjected to cyclization in an inert solvent in thepresence of a base. Cyclization which leads to risperidone is carriedout either in water in the presence of an alkali hydroxide, alkalicarbonate or alkali hydrogencarbonate, or is performed intetrahydrofuran or dioxan in the presence of an alkali hydride or alkalialkoxide. Ring-closure is preferably carried out in aqueous medium,advantageously at the boiling point of the reaction mixture.

The advantage of this process is that the formation of the dimer of theFormula VII is eliminated. However, this process is accompanied by avery serious draw-back because the piperidone derivative of the FormulaXIII formed in the synthesis can be purified only in a very complicatedmanner either by means of chromatography or via the poorlycrystallizable hydrochloride. This has the consequence that thepiperidone derivative is obtained only in relatively low yields.According to ES-P 2,050,069 the yield is only 63.1%. Moreover, we failedto reproduce the process with such yields because according to ourexperiments the yield of the hydrochloride of the piperidone derivativeof the Formula XIII is below 60%. According to ES-P 2,050,069 theconversion of the piperidone derivative of the Formula XIII into thecorresponding oxime of the Formula II is carried out with a yield of76.2%. We have succeeded in reproducing the process according to ES-P2,050,069 only with a yield of about 63%. According to ES-P 2,050,069the yield of the cyclization of the oxime of the Formula II torisperidone is 79-85%, but we could reproduce only a yield of about 75%.Thus the process disclosed in the Spanish patent is not economicaleither. The aforesaid is illustrated by comparative Example 3.

SUMMARY OF THE INVENTION

It is the object of the present invention to elaborate an economicalprocess for the preparation of risperidone.

The above object is solved by the present invention.

According to the present invention there is provided a process for thepreparation of3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneof the Formula I and pharmaceutically acceptable acid addition saltsthereof by subjecting the oxime of the Formula II to ring-closure in thepresence of an alkali hydroxide, alkali carbonate oralkali-C₁₋₄-alkoxide in a C₁₋₄-alkanol as an inert organic solvent,converting the base of the Formula I thus obtained into an acid additionsalt or setting free the base of the Formula I from an acid additionsalt thereof which comprises reacting a halogen derivative of thegeneral Formula

(wherein Hal is halogen) with the piperidine oxime derivative of theFormula V or an acid addition salt thereof in the presence of a base,and using by the ring-closure of the oxime of the Formula II formed aC₁₋₄-alkanol as inert solvent.

It has been found that risperidone can be economically prepared withhigh yields in pure form by subjecting the oxime of the Formula II tocyclization in the presence of an alkali hydroxide, alkali carbonate oralkali-C₁₋₄-alkoxide in an inert organic solvent, converting the base ofthe Formula I thus formed into an acid addition salt or setting free thebase of the Formula I from an acid addition salt thereof, whereby ahalogen derivative of the general Formula XIV (wherein Hal is halogen)is reacted with the piperidone oxime derivative of the Formula V or anacid addition salt thereof in the presence of a base and by thering-closure of the oxime of the Formula II thus formed a C₁₋₄-alkanolis used as inert solvent.

By the preparation of the oxime of the Formula II as base an inorganicbase (e.g. sodium hydrogencarbonate or potassium carbonate) or anorganic base (e.g. triethylamine or pyridine) can be used.

According to the process of the present invention after the reaction ofthe halogen derivative of the general Formula XIV and the piperidineoxime derivative of the Formula V or an acid addition salt thereof theoxime of the Formula II precipitates in crystalline form and can beconverted in the presence of a C₁₋₄-alkanol into risperidone of theFormula I with a yield of about 95%.

The process of the present invention is surprising for the personskilled in the art because it could not be foreseen that the piperidineoxime derivative of the Formula V containing two acidic hydrogen atomsor a salt thereof would be alkylated in the presence of a baseselectively only on the nitrogen atom. This is so much the moresurprising as the oxime of the Formula II can be isolated with a yieldexceeding 80%.

It is furthermore also surprising that while according to ES-P 2,050,069the ring-closure of the oxime of the Formula II is carried out with ayield of about 75% only, the process of the present invention enablesthe carrying out the cyclization with a yield of about 95%.

The advantage of the process of the present invention is that apharmaceutically pure product can be prepared in high yields.

Further details of the present invention are to be found in thefollowing Examples without limiting the scope of protection to saidExamples.

EXAMPLE 1 Preparation of3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(compound of the Formula II)

To a solution of 36.0 g (0.16 mole) of3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-onein 800 ml of acetonitrile 44.3 g of4-(2,4-difluoro-benzoyl)-piperidine-oxime-hydrochloride, 33.6 g ofsodium hydrogen carbonate and 0.66 g (4 millimoles) of potassium iodideare added. The reaction mixture is refluxed for 5 hours, cooled to roomtemperature and the solvent is removed in vacuo. The residue is taken upin 700 ml of water and extracted twice with 600 ml of dichloromethaneeach. The combined organic layers are dried over sodium sulfate andevaporated in vacuo. Thus 63.7 g of the title compound are obtained.Yield 92.5%. M.p.: 180-183° C.

EXAMPLE 2 Preparation of3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(compound of the Formula II)

One proceeds as described in Example 1 except that methanol is used inplace of acetonitrile. Thus 60.7 g of a product being identical in allrespects with the compound prepared according to Example 1 are obtained.Yield 88.2%.

EXAMPLE 3 Preparation of3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(compound of the Formula II)

One proceeds as described in Example 1 except that ethanol is used inplace of acetonitrile. Thus 62.1 g of a product being identical in allrespects with the compound prepared according to Example 1 are obtained.Yield 90.1%.

EXAMPLE 4 Preparation of3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(risperidone of the Formula I)

To a solution of 5.4 g (0.1 mole) of sodium methylate in 60 ml ofmethanol 8.6 g (0.02 mole) of3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneare added with stirring at room temperature. The reaction mixture isrefluxed for half an hour, then 100 ml of water are added. Theprecipitated crystalline product is filtered off, washed with water anddried. Thus 7.9 g of the title compound are obtained. Yield 96.3%.According to HPLC analysis the total amount of the impurities is below0.2% and the product contains no contamination in an amount above 0.1%each. The product meets the requirements of Pharmeuropa Vol. 10, No. 2,June 1988 in all respects.

EXAMPLE 5 Preparation of3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(risperidone of the Formula I)

One proceeds as described in Example 4 except that ethanol is used inplace of methanol. Thus 7.7 g of the title compound are obtained. Yield94.5%. The product is identical in all respects with the compoundprepared according to Example 4.

EXAMPLE 6 Preparation of3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(risperidone of the Formula I)

One proceeds as described in Example 4 except that 2-propanol is used inplace of methanol. Thus 7.5 g of the title compound are obtained. Yield91.4%. The product is identical in all respects with the compoundprepared according to Example 4.

COMPARATIVE EXAMPLE 1 Preparation of4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine (compound of the FormulaIV; reproduction of Example 1 Paragraph 4 of HU-P 195,793)

A suspension of 11 g of 4-(2,4-difluoro-benzoyl)piperidine-oximehydrochloride and 25 g of potassium hydroxide in 25 ml of water isheated to boiling with stirring for 2 hours. The reaction mixture iscooled to room temperature and extracted with toluene. The organic phaseis dried over anhydrous sodium sulfate and evaporated in vacuo. Theresidual crude product is recrystallized from petroleum ether. Thus 7.1g of the title compound are obtained. According to HPLC MS analysis theproduct contains 5% of4-{6-[4′-(6′-fluoro-1′,2′-benzisoxazol-3′-yl)-piperidine-1′-yl]-1,2-benzisoxazol-3-yl}-piperidine,as a contamination (compound of the Formula VI).

2.0 g of the above product is subjected to separation by columnchromatography (eluent:chloroform-methanol 9:1). Thus 57 mg of4-{6-[4′-(6′-fluoro-1′,2′-benzisoxazol-3′-yl)-piperidine-1′-yl]-1,2-benzisoxazol-3-yl}-piperidineare obtained. M.p.: 234-237° C.

pmr (DMSO-d₆): δ, ppm 1.95(m, 4H, piperidine-CH₂-3′,5′), 2.12(m, 4H,piperidine-3,5), 3.10(m, 4H, piperidine-NCH₂-2,6), 3.34(b, xH,piperidine-NCH₂-2′,6′+water), 4.03(m, 2H, piperidine-4+piperidine-4′),7.13(m, 2H, phenyl-4,5), 7.31(m, 1H, phenyl-5′), 7.68-7.80(m, 2H,phenyl-7+phenyl-7′), 8.05(m, 1H, phenyl-4′).

COMPARATIVE EXAMPLE 2

A) Preparation of3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2a]pyrimidin-4-one(risperidone of the Formula I; reproduction of Example 1 Paragraph 5 ofHU-P 195,793)

A mixture of 5.3 g (0.02 mole) of3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,4.4 g (0.02 mole) of 4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine, 8 g(0.075 mole) of sodium carbonate and 0.1 g of potassium iodide in 90 mlof N,N-dimethylformamide is heated at 85-90° C. with stirring overnight.The reaction mixture is cooled, poured into water and the precipitatedcrystalline product is recrystallized from a mixture of N,N-dimethylformamide and 2-propanol. Thus 3.6 g of the title compound are obtained.Yield 45%. M.p.: 168-170° C. According to HPLC-MS analysis the productcontains 3% of3-{2-[4-{6-(6′-fluoro-1′,2′-benzisoxazol-3′-yl)-1′-piperidinyl]-1,2-benzisoxazol-3-yl}-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneas contaminant compound of the Formula VII.

2.5 g of the above product are subjected to separation by columnchromatography (eluent: chloroform-methanol 9:1). Thus 10 mg of pure3-{2-[4-{6-(6′-fluoro-1′,2′-benzisoxazol-3′-yl)-1′-piperidinyl]-1,2-benzisoxazol-3-yl}-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-onecontamination are obtained. M.p.: 208-213° C.

B) Preparation of3-{2-[4-{6-(6′-fluoro-1′,2′-benzisoxazol-3′-yl)-1′-piperidinyl]-1,2-benzisoxazol-3-yl}-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(compound of the Formula VII)

A solution of 50 mg (0.12 millimole) of4-{6-[4′-(6′-fluoro-1′,2′-benzisoxazol-3′-yl)-piperidine-1′-yl]-1,2-benzisoxazol-3-yl}-piperidineprepared according to comparative Example 1, 27 mg (0,12 millimole) of3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,82 mg (0.6 millimole) of potassium carbonate and a catalytic amount ofpotassium iodide in acetonitrile is heated to boiling with stirring for6 hours. The reaction mixture is cooled and the solvent is evaporated invacuo. To the residue 5 ml of water are added and the mixture isextracted twice with 5 ml of dichloromethane each. The organic phase isdried over anhydrous sodium sulfate and evaporated in vacuo. Thus 50 mgof the title compound are obtained. Yield 68%. M.p.: 209-213° C. Theproduct is identical in all respects with the product isolated bychromatography according to paragraph A). pmr (DMSO-d₆): δ, ppm 1.8(m,6H, tetrahydro-pyrido[1,2-α]pyrimidin-7,8,9), 2.10(m, 4H,piperidine-CH₂-3′,5′), 2.12(m, 4H, piperidine-3,5), 2.30(s, 3H, CH₃),2.55(t, 2H, CH₂), 2.83(t, 2H, CH₂), 3.18(m, 4H, piperidine-NCH₂-2,6),3.30(b, ×H, piperidine-NCH₂-2′,6′), 4.01(m, 2H,piperidine-4+piperidine-4′), 7.11(m, 2H, phenyl-4,5), 7.30(m, 1H,phenyl-5′), 7.61-7.83(m, 2H, phenyl-7+phenyl-7′), 8.00(m, 1H,phenyl-4′).

COMPARATIVE EXAMPLE 3 Reproduction of Examples 8, 9, 10 and 11 of ES-P2,050,069

A) Preparation of3-[2-[4-(2,4-difluoro-benzoyl)-piperidino]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

A suspension of 29.2 g (0.1116 mole) of4-(2,4-difluoro-benzoyl)-piperidine-hydrochloride, 25.3 g (0.1117 mole)of3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,500 ml of acetonitrile, 19.6 g (0.2333 mole) of sodium hydrogencarbonateand 0.25 g (0.0015 mole) of potassium iodide is heated to boiling for 10hours with stirring. The reaction mixture is cooled to room temperature,to the residue 200 ml of water are added. The mixture is stirred for 30minutes and extracted with 200 ml of dichloromethane. The organic phaseis separated, dried over magnesium sulfate, filtered and the filtrate isevaporated. The oily residue thus obtained is purified as follows:

I) The oily residue is purified on a silica column; eluent:chloroform-methanol 9:1. The fractions containing the product arecollected and evaporated. The residue is dissolved in 200 ml ofdichloromethane, the solution is saturated with gaseous hydrogenchloride. The precipitated crystalline product is filtered and dried.Thus 32.1 g of the title compound are obtained. Yield 58.9%. Accordingto HPLC chromatography the purity of the product is 96.8%.

II) The oily residue is dissolved in 200 ml of dichloromethane, thesolution is saturated with gaseous hydrogen chloride. Because nocrystalline product is precipitated from the solution, the solvent isevaporated.

The residual oily product is triturated with diethyl ether for a longerperiod of time. Crystallization is initiated by seeding with a crystalof the desired compound. Thus 27.9 g of the title compound are obtained.Yield 51.2%. According to HPLC analysis the purity of the product is94.8%.

B) Preparation of3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

To a solution of 7.0 g (0.0143 mole) of3-[2-[4-(2,4-difluoro-benzoyl)-piperidino]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,70 ml of pyridine, 5.4 g (0.0777 mole) of hydroxylamine hydrochlorideand 100 ml of ethanol 1.6 g (0.0286 mole) of potassium hydroxide areadded. The reaction mixture is heated to boiling for 10 hours, cooled toroom temperature and the solvent is removed in vacuo. To the residue 100ml of water are added and the mixture is extracted with 100 ml ofdichloromethane. The organic phase is washed twice with 50 ml of watereach, dried over anhydrous magnesium sulfate and evaporated. Theresidual crude product is recrystallized from ethyl acetate. Thus 4.2 gof3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneare obtained. Yield 65.1%. According to HPLC analysis the purity of theproduct is 97.2%.

C) Preparation of3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

To a suspension of 40 mg (0.9166 millimole) of 55% sodium hydride and 2ml of tetrahydrofurane 0.1089 g (0.2532 millimole) of3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneis added. The reaction mixture is heated to boiling for an hour,whereupon 5 ml of water are added and the mixture is extracted twicewith 10 ml of dichloromethane each. The combined organic phases aredried over magnesium sulfate and evaporated in vacuo. Thus 80 mg of thetitle compound are obtained, yield 77%. According to HPLC analysis thepurity of the product is 97.5%.

D) Preparation of3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

A solution of 1 g (0.0023 mole) of3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneand 1 g of potassium hydroxide in 10 ml of water is heated to boilingfor an hour. The reaction mixture is cooled to room temperature andextracted twice with 10 ml of dichloromethane each. The organic phase isevaporated. Thus 0.70 g of3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimid-in-4-oneare obtained, yield 73.5%. According to HPLC analysis the purity of theproduct is 96.4%.

1. Process for the preparation of3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-oneof the Formula

and pharmaceutically acceptable acid addition salts thereof bysubjecting the oxime of the Formula

to ring-closure in the presence of an alkali hydroxide, alkali carbonateor alkali-C₁₋₄-alkoxide in an inert organic solvent, converting the baseof the Formula I thus obtained into an acid addition salt or settingfree the base of the Formula I from an acid addition salt thereof whichcomprises reacting a halogen derivative of the general Formula

(wherein Hal is halogen) with piperidine oxime derivative of the Formula

or an acid addition salt thereof in the presence of a base, and using bythe ring-closure of the oxime of the Formula II formed a C₁₋₄-alkanol asinert solvent.
 2. Process according to claim 1 which comprises using ahalogen derivative of the general Formula XIV wherein Hal stands forchlorine.
 3. Process according to claim 1 which comprises using thehydrochloride salt of the piperidine oxime derivative of the Formula V.4. Process according to claim 1 which comprises using sodiumhydrogencarbonate as base.
 5. Process according to claim 1 whichcomprises using methanol as C₁₋₄-alkanol.
 6. Process according to claim1 which comprises using ethanol as C₁₋₄-alkanol.
 7. Process according toclaim 1 which comprises using isopropanol as C₁₋₄-alkanol.